1. Field of the Invention
The present invention relates generally to the fields of cancer therapy.
2. Description of Related Art
Colorectal cancer is the second most common cause of cancer-related death in the United States (Jemal et al., 2005). The benchmark median overall survival of patients receiving first-line and second-line combination chemotherapy for metastatic colorectal cancer is currently 17-20 months and 10-12 months, respectively (Douillard et al., 2000; Goldberg et al., 2004; Tournigand et al., 2004; Rothenberg et al., 2003; Hurwitz et al., 2004; Giantonio et al., 2005; Cunningham et al., 2004; Diaz Rubio et al., 2005). Unfortunately, the five year overall survival was merely 5-8%.
Various combination therapies have been used to address this form of cancer. Combining bevacizumab or cetuximab with cytotoxic chemotherapy produced response rate to 60-80%, converting more patients to be surgically resectable, but not overall CR rate ranging between 2-10% (Hurwitz et al., 2004; Diaz Rubio et al., 2005; Hochster, 2006). However, little is known about natural history of the 2-10% CR patients from chemotherapy, as majority do relapse within two years. The natural history of these surgical CR patients may be the closest approximation to that of the CR patients rendered by chemotherapy. Even though metastatic colorectal cancer is a systemic disease, selecting patients with liver only metastasis to undergo surgical resection leads to a five-year survival rate of 30-40% (Fong, 2000; Topham and Adam, 2002). In reality, only 2,300 (4%) of 60,000 patients with recurrent colorectal cancer per year may be “cured” with surgery among the 6,800 (11%) resectable patients. Five year overall survival rate for patients who had R0 (margin free) resection of metastasis was 40% compared to 0% for those with R1/R2 (close or gross margin resection or with radiofrequency ablation alone) (Abdalla et al., 2004). Adam et al reported a five-year overall survival of 34% for patients with unresectable liver metastatasis who then achieved surgical resection after response with chemotherapy (Adam et al., 2001). Adjuvant hepatic directed therapy in patients with resected liver metastasis remained controversial and appeared to impact only two-year hepatic recurrence free survival (Kemeny et al., 1999). Not surprisingly, the five year survival for patient with best tumor characteristics (solitary tumor <5 cm; disease free interval >12 months; CEA<200; node negative primary tumor) approached 60% (Fong et al., 1999). Intensive neoadjuvant and adjuvant chemotherapy in 47 patients with resectable liver metastasis produced response rate of 77% and median progression free survival of 21 months, and five year survival of 60% (Taieb et al., 2005). Much improvement for survival are needed for those with resectable liver metastasis and more so for those with unresectable metastases.
Some further combination chemotherapy often consists of 5-fluorouracil (5-FU), administered via infusional pumps and either irinotecan or oxaliplatin with bevacizumab or cetuximab (Hurwitz et al., 2004; Giantonio et al., 2005; Cunningham et al., 2004; Diaz Rubio et al., 2005). These treatments require placement of indwelling catheters and infusion pumps and produce a broad spectrum of serious toxicities, including myelosuppresion, diarrhea, neuropathy, skin rash, hypertension and rare bowel perforations (Douillard et al., 2000; Goldberg et al., 2004; Tournigand et al., 2004; Rothenberg et al., 2003; Hurwitz et al., 2004; Giantonio et al., 2005; Cunningham et al., 2004; Diaz Rubio et al., 2005). An equally effective, less toxic treatment that can be orally administered would be most appealing to patients (Borner et al., 2002). Capecitabine (XELODA®; Roche Pharmaceuticals, Nutley, N.J.) is an oral fluoropyrimidine pro-drug that is preferentially activated to 5-FU in tumor tissue. First-line treatment of metastatic colorectal cancer with capecitabine produced 25% response rates and improved toxicity profiles without overall survival benefits (12 months) compared with bolus 5-FU (Van Cutsem et al., 2001; Hoff et al., 2001).Therefore, capecitabine is often combined with intravenously injected agents such as oxaliplatin or irinotecan for improved survival, so advantage of oral convenience is not fully exploited (Patt et al., 2004; Cassidy et al., 2004).
Like protracted 5-FU infusion, capecitabine at 1250 mg/m2/day bid for two weeks every 3 weeks was also associated with increased incidence of hand-foot syndrome (HFS) occurring in 54% of the patients with 18% being grade 3 (Van Cutsem et al., 2001; Hoff et al., 2001; Meta-Analysis Group In Cancer, 1998). HFS is characterized by painful, erythematous swelling of the hands and feet that progresses to blisters within the first few weeks of starting therapy (Abushullaih et al., 2002). HFS is not life threatening, but may significantly interfere with daily activities and frequently reoccurs even after the second or third dose reductions (Abushullaih et al., 2002). There are no proven measures for HFS except for dose schedule modification and topical emollient (Nagore et al., 2000). Claims that high dose pyridoxine could prevent HFS have not been substantiated (Fabian et al., 1990). Because HFS possesses erythema, swelling, heat and pain, we postulated that HFS is an inflammatory process as a result of cyclooxygenase-2 (COX-2) activation, which is also prognostic marker for colorectal cancer progression and survival (Lin et al., 2002; Howe and Dannenberg, 2002; Sheehan et al., 1999). In xenograft models, adding celecoxib (XCEL) (CELEBREX®; Pfizer, New York, N.Y.) a selective COX-2 inhibitor, to chemotherapy or radiation therapy significantly increased antitumor efficacy compared to either treatment modality alone (Cianchi et al., 2001; Masferrer et al., 2000; Sheng et al., 1998; Milas, 2003). The preliminary findings suggested reduced HFS and improved survival for those with metastatic colorectal cancer who took XCEL (n=32) versus those who took capecitabine alone (n=35); however, more patients in the XCEL group receiving chemo-radiation (Lin et al., 2002). Given the survival benefits and unexpected response including complete responses, we expanded the study cohort (including the initial 32 patients who had XCEL) and performed analysis on the time course of HFS, response rate and survival stratified according to their prior chemotherapy or radiation.
The inventors reported in a retrospective study of 66 patients with metastatic colorectal cancer who underwent XCEL+/−radiation therapy experienced reduced toxicities notably hand-foot syndrome and improved overall survival in both first-line and second-line setting. Given that nineteen (29%) of sixty-six patients unexpectedly achieved CR with XCEL alone (n=9) or with radiation (n=12) including six were surgical CR after response, the inventors undertook a detailed analysis of tumor characteristics, pattern and duration of CR and relapse in relationship to diagnosis of cancer, first-line therapy, XCEL and surgery.